Process or the preparation of 4-amino 1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-hydroxymethyl-cyclopent-2-Enyl)-1H-pyrimidin-2-one

ABSTRACT

Processes for the preparation of 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-hydroxymethyl-cyclopent-2-enyl)-1H-pyrimidin-2-one (13, RX-3117) and its intermediates are described.

This application is a continuation of U.S. patent application Ser. No.14/216,242, filed on Mar. 17, 2014, which claims the benefit of U.S.Provisional Application No. 61/800,475, filed Mar. 15, 2013, which arehereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to the process for the preparation of4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-hydroxymethyl-cyclopent-2-enyl)-1H-pyrimidin-2-oneand its intermediates.

BACKGROUND OF THE INVENTION

4-Amino-1((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-hydroxymethyl-cyclopent-2-enyl)-1H-pyrimidin-2-one(RX-3117)

is disclosed in U.S. Pat. No. 7,405,214, which describes a syntheticmethod and method of treatment as well. The method described in U.S.Pat. No. 7,405,214 includes a total of 11 steps to synthesize the(3R,4R,6aR)-tert-Butyl-(5-fluoro-2,2-dimethyl-6-trityloxymethyl-4,6a-dihydro-3aH-cyclopenta[1,3]dioxol-4-yloxy)-diphenyl-silanefrom D-ribose, which is an important intermediate for the synthesis of4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-hydroxymethyl-cyclopent-2-enyl)-1H-pyrimidin-2-one.U.S. Pat. No. 7,405,214 uses an expensive catalyst which poses achallenge for implementation in plant production.

SUMMARY OF THE INVENTION

The present invention discloses a short route for the preparation of4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-hydroxymethyl-cyclopent-2-enyl)-1H-pyrimidin-2-onethrough(3R,4R,6aR)-tert-butyl-(5-fluoro-2,2-dimethyl-6-trityloxymethyl-4,6a-dihydro-3aH-cyclopenta[1,3]dioxol-4-yloxy)-diphenyl-silane.Each step of the method is described individually and the invention canbe considered as any one of the individual steps or any combination ofsteps taken together.

In embodiments, the invention is a process for the preparation of4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one(13) by reacting 4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one(12) with acid, for example HCl.

Embodiments of the process can include preparing4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one(12) by reacting(3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (11) with cytosine.

Embodiments of the process can include preparing(3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (11) by reacting (3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(10) with MsCl.

Embodiments of the process can include preparing(3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(10) by deprotection of tert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(9).

Embodiments of the process can include preparation oftert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(9) by reactingtert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (8) with NFSI(N-fluorobenzenesulfonimide).

Embodiments of the process can include preparation of(3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(9) by conversion of tert-butyl(((3 aR, 4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(8) to a boronic acid intermediate followed by hydrolysis and reactionwith 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (Selectfluor®). In some embodiments The boronicacid intermediate is[(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronicacid (9c-1), and prepared by reaction oftert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(8) with trimethylborate. In some embodiments, the boronic acidintermediate is[(3aR,6S,6aR)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy-tert-butyl-diphenyl-silane(9c-2), prepared by reacting tert-butyl(((3aR, 4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(8) with 4,4,5,5-tetramethyl-1,3,2 dioxaborolane.

Embodiments of the process can include preparingtert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(8) by reacting (3 aS, 4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(7) with t-BDPSCl.

Embodiments of the process can include preparing(3aS,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(7) by reacting (3aR,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one (6) with CeCl₃ and NaBH₄.

Embodiments of the process can include preparing(3aR,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one(6) by oxidizing(1R,4S,5S)-2-iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol(5). The oxidizing can be with, for example, pyridinium dichromate(PDC).

Embodiments of the process can include preparing(1R,4S,5S)-2-iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol(5) by reacting1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone(4) with n-BuLi.

Embodiments of the process can include preparing1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone(4) by oxidizing1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol(3). The oxidizing step can be conducted, for example, with pyridiniumdichromate (PDC) or by Swern oxidation using diisopropylcarbodiimide,pyridine, trifluoroacetic acid (CF₃COOH), and sodium hypochlorite(NaOCl).

Embodiments of the process can include preparing1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol(3) by reacting(3aR,6aR)-2,2-dimethyl-6-((trityloxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-ol(2) with iodoform.

Embodiments of the process can include preparing the(3aR,6aR)-2,2-dimethyl-6-((trityloxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-ol(2) by reacting(3aR,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol(1) with trityl chloride.

Embodiments of the process can include preparing(3aR,6aR)-2,2-dimethyl-6-((trityloxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-ol(2) by reacting(3aR,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol(1) with trityl chloride.

Embodiments of the process can include preparing(3aR,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol(1), for example by reacting D-ribose with 2,2-dimethoxypropane or byreacting D-ribose with acetone in the presence of acid.

Further objectives and advantages, as well as the structure and functionof preferred embodiments will become apparent from a consideration ofthe description, and non-limiting examples that follow.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the invention are discussed in detail below. Indescribing embodiments, specific terminology is employed for the sake ofclarity. However, the invention is not intended to be limited to thespecific terminology so selected. While specific exemplary embodimentsare discussed, it should be understood that this is done forillustration purposes only. A person skilled in the relevant art willrecognize that other components and configurations can be used withoutparting from the spirit and scope of the invention. All references citedherein are incorporated by reference as if each had been individuallyincorporated.

Nucleosides are known to be the subunits in DNA and RNA macromolecules,and also play roles in neurotransmission (Baldwin, S. A.; Mackey, J. R.;Cass, C. E.; Young, J. D. Mol. Med. Today 1999, 5, 216) andcardiovascular activity (Shryock, J. C.; Belardinelli, L. Am. J.Cardiol. 1997, 79, 2) and as signaling molecules (Schachter, J. B.;Yasuda, R. P.; Wolfe, B. B. Cell Signaling 1995, 7. 659) in addition totheir function in cellular biosynthetic pathways. Nucleosides and theiranalogues are used for the treatment of cancer, anti-viral infectionsand AIDS. For example, Gemcitabine (Giessrigl, B. et al. Human MolecularGenetics, 2012, 21(21), 4615-4627; Hertel, L. W.; Kroin, J. S.; Misner,J. W.; Tustin, J. M. J. Org. Chem, 1988, 53, 2406; Plunkett, W.; Huang,P.; Ganghi, V. Nucleosides Nucleotides, 1997, 16, 1261) is approved forthe treatment of pancreatic cancer and AZT(3′-Azido-2′3′-dideoxythymidine) is approved for the treatment of HIV(human immunodeficiency virus). Other examples include FMAU(Fluoro-L-arabinofuranosyl)-5-methyluracil, Clevudine) (Wiebe, L. I. etal. Current Radiopharmaceuticals, 2012, 5(1), 38-46; Chu, C. K. et al.Antimicrob. Agents Chemother., 1995, 6, 979) FIAC (Fiacitabine FluoroL-arabinofuranosyl)-5-iodocytosine) (Prichard, Mark N.; AntiviralResearch, 2006, 71(1), 1-6), FLT (Alovudine, 3′-Fluoro-thymidine)(Agarwal, H. K.; Buckheit, K. W.; Buckheit, R. W.; Parang, K. Bioorganic& Medicinal Chemistry Letters, 2012, 22(17), 5451-5454; Balzarini, J.;Baba, M., Pauwels, R., Herdewijn, P., De Clercq, E. Biochem. Pharmacol,1988, 37, 2847) F-ddC(2,3-dideoxy-2-fluoro-β-d-threo-pentofuranosyl)-cytosine,2-fluorodideoxycytidine) (Okabe, M.; Sun, R.-C; Zenchoff, G. B. J. Org.Chem. 1991, 56, 4392) and SFDC(1-(2-Deoxy-2-C-fluoromethylarabinofuranosyl)cytosine) (Yoshimura Y.;Saitoh, K.; Ashida, N.; Sakata S.; Matsuda, A. Bioorganic Med. Chem.Lett., 1994, 4, 721).

Nucleosides can be classified into two major subtypes, N-nucleosides andC-nucleosides, where the bond between the anomeric carbon of the sugarmoiety and the base are through the nitrogen or the carbon of the base,respectively. In addition, nucleosides where the sugar ring oxygen isreplaced with sulfur, phosphorus, nitrogen and carbon are termedthionucleosides (Yokoyama, M. Synthesis, 2000, 1637), phosphonucleosides(Yamashita, M.; Kato, Y.; Suzuki, K.; Reddy, P. M.; Oshikawa, T.Abstracts of 29^(th) Congress of Heterocyclic Chemistry, 1998, 461),azanucleosides (Yokoyama, M.; Momotake, A. Synthesis, 1999, 1541) andcarbocyclic nucleosides (Akella, Lakshmi B.; Vince, Robert FromTetrahedron (1996), 52(25), 8407-8412; Crimmins, M. T. Tetrahedron,1998, 54, 9229) respectively.

Neplanocin A and (-) Aristeromycin, isolated from natural sources, aremembers of the carbocyclic nucleosides sub-family. Despite of theirpotent anti-viral activity only limited structure activity relationship(SAR) studies of these nucleosides has been carried out. The main reasonfor this shortage is the synthetic difficulty in preparing theD-carbasugars, thus modifications have mainly been done on the basemoiety.

Conventional methods of synthesizing carbasugars have the drawback beinglengthy routes which do not allow for large scale preparation. Forinstance: in 2000 Chu's group converted D-glyceraldehyde into E-alkene,an intermediate, in eight (8) steps. The intermediate underwentintramolecular nucleophilic substitution to furnish thefluoro-cyclopentenyl framework (Gumina, G.; Chong, Y.; Choi, Y. Chu, C.K. Org. Lett., 2000, 2, 1229). A similar intermediate was used to give1,6-diene which underwent ring cyclization metathesis (RCM) usingGrubbs' catalyst (Chong, Y.; Gumina, G.; Chu, C. K. Tetrahedron:Asymmetry, 2000, 11, 4853). In 2005 Schmeller and Yin (Yin. X.-Q.;Schneller, S. W. Tetrahedron Lett., 2005, 46, 7535) reported thesynthesis of 6′β-fluoroaristeromycin starting from optically active4-hydroxy-2-cyclopenten-1-yl acetate in a similar procedure describedearlier by Prisbe et al. (Madhavan, G. V. B.; McGee, D. P. C.;Rydzewski, R. M.; Boehme, R.; Martin, J. C.; Prisbe, E. J. Med. Chem.,1988, 31, 1798). These procedures start from a functionalizedcyclopentane/cyclopentene skeleton, which is subjected to a sequence ofchemical manipulations (e.g., protection strategies, epoxidation, azideformation and fluorination via nucleophilic substitution) to result inthe target fluoro-carbocyclic-nucleoside.

Other strategies for fluorocarbocyclic nucleosides fromcyclopentene-containing frameworks include Roberts synthesis from abicyclic ketone system to a 6′-fluorocarbocyclic nucleoside (Payne, A.N.; Roberts, S. M. J. Chem. Soc., Perkin Trans. 1, 1992, 2633),Samuelsson's work starting from enantiomerically pure(3S,4R)-bis(hydroxylmethyl)cyclopentannone ethylene glycol ketal toprovide the fluorocarbocyclic moiety in 10 steps (Wachtmeister, J.;Muhlman, A.; Classon, B., Samuelsson B. Tetrahedron 1999, 55, 10761) andBiggadike and Borthwick's route to convert carbocyclic2′β-fluoro-guanosine derivative into another fluorocarbocyclicnucleoside (Biggadike, K.; Borthwick A. D. J. Chem. Soc., Chem. Commun.1990, 1380).

In 2008 Schneller's group reported the synthesis of5′-fluoro-5′-deoxyaristeromycin through Mitsunobu coupling of protectedadenine with 4-fluoromethylcyclopentan-1-ol, which was prepared ineleven (11) steps from ribose, and which was transferred into a dienesystem to enable RCM (Li, W.; Yin, X.; Schneller, S. W. Bioorg. Med.Chem. Lett. 2008, 18, 220).

In 2003 Jeong's group reported the synthesis of fluoroneplanocin A whichwas found more potent than the parent Neplanocin A (Jeong, L. S. et al.J. Med. Chem., 2003, 46, 201). The key intermediate3-hydroxymethyl-D-cyclopentenone was prepared from ribose in seven (7)steps involving 2,2-O-isopropylidenetion, Wittig reaction followed bySwern oxidation, Grignard reaction and RCM to form the cyclopentene ringas a mixture of α/β tertiary OH groups. Only the β isomer underwentoxidative rearrangement into the synthon (Choi, W. J, et al.Nucleosides, Nucleotides, and Nucleic Acids, 2005, 24(5-7), 611-613). In2005 Jeong's group reported the synthesis and the anti-tumor activity ofa novel fluorocyclopentenyl-cytosine. The synthesis utilized the lattersynthon, which was converted to fluorocyclopentenol in four (4) steps:iodination with I₂; stereo and regioselective reduction (of α,β-unsaturated ketone); protection of the resulting OH group with TBDPS(tert-butyldiphenylsilyl ether); and electrophilic fluorination at thevinyl position via metal halogen exchange, withN-fluorobenzensulfonimide (NFSI) and n-BuLi (Jeong, L. S. et al.Nucleosides, Nucleotides, and Nucleic Acids, 2007, 26, 713-716). Thefinal pyrimidine nucleoside (example 13) was obtained by coupling ofprotected uracil derivative with the fluorocyclopentenol under Mitsunobuconditions followed by base transformation (Uracil into Cytosine) inthree (3) steps (i) POCl₃, Et₃N; ii) 1,2,4-triazole; iii) NH₄OH).

In a method according to the present invention4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-hydroxymethyl-cyclopent-2-enyl)-1H-pyrimidin-2-one(example 13 compound) is synthesized using the reaction scheme 1.Briefly,(3aR,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol(1) is prepared by reacting D-ribose with acetone in the presence ofacid or by reaction of D-ribose with 2,2-dimethoxypropane, which istritylated to form(3aR,6aR)-2,2-dimethyl-6-((trityloxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-ol(2). The tritylate 2 is reacted with iodoform to provide diiodovinylcompound1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol(3) which is then oxidized by Swern oxidation or using pyridiniumdichromate (PDC) to provide1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone(4). Ring closure of 4 is accomplished by the addition of, for example,n-BuLi to provide(1R,4S,5S)-2-Iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol(5), which is oxidized to(3aR,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one(6), which can be isolated before reduction to(3aS,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(7), and protection of the subsequently formed hydroxyl group with, forexample, t-BDPSCl (TBDPSCl; tert-butyldiphenyl chlorosilane) to affordtert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(8).

The protected compound 8 can be converted to the fluorinated compoundtert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(9) using a variety of methods. In a first embodiment, conversion isaccomplished by reaction with N-fluorobenzensulfonimide (NFSI).Alternatively, protected compound 8 can be converted to a boraneintermediate that can be hydrolyzed and fluorinated using ofSelectfluor® (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate)). The borane intermediate can be, for example,[(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronicacid (9c-1), prepared by reacting the protected compound 8 withtrimethylborate, or[(3aR,6S,6aR)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy-tert-butyl-diphenyl-silane(9c-2), prepared by reacting the protected compound 8 with4,4,5,5-tetramethyl-1,3,2 dioxaborolane.

The fluorinated compound 9 is deprotected to(3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(10), for example by reaction with tetra-n-butylammonium fluoride(TBAF), and mesylated to give(3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (11). The mesylate 11 is reacted with cytosine to give4-amino-1-(3 aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one(12) which is fully deprotected to provide4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one(13).

The reactions in scheme 1 can be accomplished utilizing the reactionconditions described in more detail herein and as shown in the examples.However, the examples are intended to be illustrative and not limiting.Persons of ordinary skill in the art will recognize other methods toaccomplish the reactions and conversions described herein and willrecognize certain equivalents, for example use of alternative protectinggroups, may be substituted for the specific reagents, protecting groups,etc. described herein.

This method does not require the use of expensive Grubbs's catalyst (atransition metal (e.g., ruthenium) carbene complex), to effectring-closure-metathesis (RCM) in construction of the carbasugar(C-carbohydrate ring, that is, the ring O is replaced by C).Furthermore, this method does not require a Grignard reaction tointroduce a vinyl moiety to form the diene system to enable the RCM.During this latter step, the exothermic Grignard reaction at scalepresents substantial safety issues. Furthermore, Grignard reactions aredifficult to initiate and it is difficult to detect when initiation hasoccurred. This can result in variation from batch to batch, and, ifinitiation is delayed, there might be an effect on the impurity profile.The heterogeneous Grignard reaction might result in mixing issues in ascaled-up process. The alternative ring closure method set forth inScheme 1 is safer when scaled up, more time and cost effective, does notrequire heating, does not require a long duration of reaction, and doesnot require expensive 2^(nd) generation Grubbs' catalyst. As such, thesynthesis set forth in Scheme 1, above, has advantages over othersynthetic schemes in the art.

In Scheme 1, iodoform is reacted with compound 2 under Wittig conditionsto give compound 3 which is oxidized into 4, so that no separateiodination step is required. Compound 4 can undergo intramolecular ringclosure and entry into the cyclopentenol 5. The synthesis of Scheme 1 isshorter than other synthetic schemes in the art. Scheme 1 is scalablefor plant manufacturing and adaptable to manufacturing of compound 9 inkilogram scale, as set forth in the examples below. The presentinventive route avoids the use of potentially hazardous POCl₃ and NH₄OH.To our knowledge, there is no previous example in the scientific andpatent literature of a direct coupling of cytosine with a carbasugarderivative.

Several different N⁴-acylated cytosines were prepared: acetyl,trifluoroacetyl, benzoyl, 4-methoxy benzoyl and BOC, as well as thesilylated derivatives bistrimethylsilyl cytosine and bistrimethylacetylcytosine. These were reacted with various derivatives of the alcohol ofcompound 10 (such as the mesylate). A nearly 1:1 mixture ofN¹-alkylated/O-alkylated cytosine was obtained.

The reaction schemes set forth herein include a direct transformationwith desired region-selectivity to form, for example, the compound 13(4-amino-1-((1S,R4,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)cyclopent-2-en-1-yl)pyrimidin-2(1H)-one),including a novel entry into carbasugars.

A reaction using the mesylate 11 and displacement with cytosine underKO^(t)Bu/DMSO conditions gave complete conversion, approximately 90% infavour of the desired N¹-alkylated product, with the remainder being theO-alkylated product. The two were readily separated by chromatography.After subsequent trityl and acetonide deprotection, compound 13 wasafforded with chemical purity of 98.34% area in 50% yield from alcohol10.

The synthetic process according to the present invention has advantagesover syntheses in the prior art, for example in terms of shorter route,avoidance of expensive catalyst, ability to be adapted for bulkproduction and avoidance of the separations using silica gel columnchromatographic techniques.

EXAMPLES

The following Examples, exemplify some of the embodiments according tothe present invention. The following Examples are not to be consideredto limit the invention in any way. For example, a person skilled in theart will understand that in certain instances polar (e.g., water,dimethylsulfoxide, dimethylformamide, and methanol), apolar (e.g.,hexane, ethyl acetate, tetrahydrofuran, and dichloromethane), protic(e.g., water, methanol, and ethanol), aprotic (e.g., tetrahydrofuran,ethyl acetate, dimethylformamide, and dimethylsulfoxide), electron-pairdonor (e.g., tetrahydrofuran and methanol), and non-electron-pair donorsolvents other than those set forth in the process steps below can beused. For example, a person skilled in the art will understand that incertain instances the ionic strength of a solution may be varied fromwhat is set forth in the process steps below can be used. For example,in certain instances, a salt or salts different than those set forth inthe process steps below can be used to induce precipitation of acompound or compounds. In certain instances, a precipitation step can beskipped or eliminated, in other instances, a precipitation step can beadded. In certain instances, a single solvent may be substituted for amixture of solvents; in other instances, a mixture of solvents may besubstituted for a single solvent. For example, a person skilled in theart will understand that in certain instances temperatures other thanthose set forth in the syntheses below can be used; for example,temperatures that are 1, 2, 5, 10, 15, 20, 25, or 30° C. greater orlesser than the temperatures set forth can be used in certain instances.For example, “ambient temperature” can mean about 5, 10, 15, 20, 22, 25,30, 35, 40, or 45° C. For example, “room temperature” can mean about 5,10, 15, 20, 22, 25, 30, 35, 40, or 45° C. For example, a person skilledin the art will understand that in certain instances pH values otherthan those set forth in the syntheses below can be used; for example, apH that is 0.1, 0.2, 0.5, 1, 2, 3, 4, or 5 pH units greater or lesserthan the pH value set forth can be used in certain instances. Forexample, a person skilled in the art will understand that in certaininstances times for reaction, stirring, dissolution, or other processsteps other than those set forth in the syntheses below can be used; forexample, times that are 25%, 33%, 50%, 67%, 80%, 125%, 150%, 200%, 300%,or 400% of those set forth can be used in certain instances. Forexample, a person skilled in the art will understand that in certaininstances the proportion of a reactant to another reactant and/or theratio of a reactant to solvent other than those set forth in thesyntheses below can be used. For example, in certain instances theweight percentage of one or more reactants, solvents, precipitationagents, or other materials or compounds in a mixture may be 25%, 33%,50%, 67%, 80%, 125%, 150%, 200%, 300%, or 400% of those set forth in thebelow examples. For example, a person skilled in the art will understandthat in certain instances a reactant other than indicated in thesyntheses below can be used. For example, a person skilled in the artwill understand that in certain instances a reactant and/or a solvent ofgreater or lesser purity than indicated in the syntheses below can beused. For example, a person skilled in the art will understand that incertain instances a process step, such as a purification, separation, orextraction step may be modified from those set forth below or that adifferent process step may be substituted. For example, a person ofskill in the art will understand that a drying agent or agents differentthan that or those specified can be substituted, and or that a nearlycomplete (high), partial, or no vacuum can be substituted for a pressurecondition specified in certain instances. For example, a person skilledin the art will understand that in certain instances molecular sievesother than those set forth below may be used. For example, in certaininstances, activated carbon, silica gels, clays, glasses, and zeolitesmay be substituted for each other. For example, a person skilled in theart will understand that in certain instances separation techniquesand/or chromatographic techniques other than those set forth below maybe used. For example, a person skilled in the art will understand thatin certain instances chromatographic media and/or substrates other thanthose set forth below may be used. For example, a person skilled in theart will understand that in certain instances a process step, such as asynthetic and/or purification step, may be split into two or moreseparate process steps, and that in other instances two or more separateprocess steps may be combined into a single process step. For example, aperson skilled in the art will understand that in certain instances aprocess step, such as a purification step, may be skipped or eliminated,and that in other instances a process step, such as a purification step,may be added. For example, a person skilled in the art will understandthat in certain instances process steps, such as synthetic and/orpurification steps, can be performed in a different order than set forthbelow. For example, a person skilled in the art will understand that incertain instances a different analytical technique than those set forthbelow or an analytical technique run under different conditions thanthose set forth below can be used. In certain instances, an analyticalstep set forth below (for example, to determine the amount orconcentration of a product component) can be skipped, in other instancesan analytical step can be added. A person skilled in the art willunderstand that such modifications to reactants used, solvents used,reaction conditions, such as temperature, time, and concentrations andrelative proportions of reactants and/or solvents, synthetic steps,purification, separation, and/or extraction steps and techniques,materials used in separation and/or purification steps, and analyticaltechniques can be made to further optimize process parameters such asyield and purity and overall process economics (such as overall time andnumber of steps and cost of materials, such as reactants and solvents,used), and that such modifications are within the scope of the presentinvention and embodiments of the invention set forth herein.

The reactions disclosed herein are demonstrated for specific compounds.However, these reactions can apply to other structurally relatedcompounds. Persons skilled in the art will recognize that the reactionscan be used on structurally similar compounds, for example, when used inthe field of carbasugars.

General

All chemicals were reagent grade and were purchased from AldrichChemical Company (Milwaukee, Wis.) or Sigma Chemical Company (St. Louis,Mo.). Solvents were routinely distilled prior to use. Anhydroustetrahydrofuran was distilled from sodium/benzophenone prior to use.

Proton NMR spectra were recorded on a Varian-400 MHz spectrometer indeuterated solvents such as DMSO-d₆, CDCl₃, acetonitrile-d₃ oracetone-d₆. Chemical shifts are reported in parts per million (ppm) withtetramethylsilane (TMS) as an internal standard at zero ppm. Couplingconstants (J) are given in hertz (Hz) and the abbreviations s, d, t, q,and m refer to singlet, doublet, triplet, quartet and multiplet,respectively. TLC was performed on Merck precoated 60F₂₅₄ plates. Columnchromatography was performed using silica gel 60 (230-400 mesh, Merck).

Example 1 Example 1a(3aR,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol(1)

Into a 2000 L reactor was charged acetone (1200 L) and2,2-dimethoxypropane (125 kg, 1200 mol, 1.2 eq), followed by D-ribose(150 kg, 999 mol). The mixture was stirred at ambient temperature. p-TSA(p-toluene sulfonic acid) (9.6 kg, 49.5 mol, 0.05 eq) was added inportions over 40 minutes. The reaction mixture was heated at 30° C. andmonitored by TLC every hour. After 14 hours, TLC indicated completeconversion. A sample from the reaction mixture and standard samples forribose and ribose acetonide were applied to a commercial silica gel TLCplate, and the plate was run in the mobile phasedichloromethane/ethanol=8:1. The plate was then sprayed with 10% H₂SO₄in ethanol and heated using a heat gun. Ribose-related compounds gavedark spots on the plate. The R_(f) for Ribose was ˜0.1, while R_(f) forribose acetonide (1) was usually 0.3˜0.35. To the reaction mixture wasadded triethylamine (8.1 kg, 0.08 eq). Acetone was distilled undervacuum (water bath temperature <60° C.) over 12 hours. The residue wasdiluted with dichloromethane (300 L). The mixture was stirred for 0.5hour at ambient temperature, and then solvent was removed under vacuumover 4 hours. This operation was repeated once, and the residue was usedin next step without further purification. ¹H NMR (400 MHz, CD₃OD) β1.31 (s, 3H, CH₃), 1.44 (s, 3H, CH₃), 3.59 (dd, J=5.6, 12.0 Hz, 1H,HOCHH), 3.63 (dd, J=4.8, 12.0 Hz, 1H, HOCHH), 4.19 (irregular t, J=4.4,5.2 Hz, 1H, 4-H), 4.52 (d, J=6.0 Hz, 1H, 3-H), 4.77 (d, J=6.0 Hz, 1H,2-H), 5.26 (s, 1H, anomeric H). Anal. calcd for CH₈H₁₄O₅: C, 50.52; H,7.42. Found: C, 50.48; H, 7.36; [α]²⁵ _(D)−36.2 (c 1.45, acetone) [lit.,[α]²⁵ _(D)-37 (c 0.53, acetone)].

Example 1b

To the 1000 L reactor 1 was charged 312 kg acetone and 40.0 kg D-Ribose,and the reaction mixture was cooled to 5-10° C. 1.60 kg of concentratedH₂SO₄ was added drop wise at 5-10° C. and the mixture was stirred at5-10° C. for 1 hour after which time the mixture was allowed to warm to25-30° C. and stirred for an additional 2 hrs. HPLC (ELSD) showed that3.5% of D-ribose remained. The reaction mixture was cooled to <−5° C.and slowly added into a mixture of 160 kg of acetone, 8.5 kg Na₂CO₃, 20kg Na₂SO₄ in 1000 L reactor 2 and the mixture was stirred at 5±5° C. for1 h to result in neutralization (pH>7). The mixture was filtered toremove Na₂SO₄, extra Na₂CO₃ and salt, and the cake was washed withacetone (10 kg×3). The combined acetone solution (504 kg, of which 702 gsampled was concentrated to 74.2 g residue to estimate 53.3 kg of totalcrude 1) was concentrated under vacuum at <20° C. followed by additionof 120 kg DCM (dichloromethane) and removal of the solvent at 20-25° C.under vacuum to furnish crude 1 (KF, 0.4%) to which 692 kg DCM wereadded. The solution was used directly in the next stage.

Example 2a(3aR,6aR)-2,2-dimethyl-6-((trityloxy)methyptetrahydrofuro[3,4-d][1,3]dioxol-4-ol(2)

To the residue from the last step (Example 1a) (˜189 kg, 999 mol) in the2000 L (Example 1a) reactor was charged 900 L of DMF(dimethylformamide), and the solution was stirred 0.5 hour at ambienttemperature. To the stirred solution was added trityl chloride (Trt-Cl,336 kg, 1200 mol, 1.2 eq), triethylamine (202 kg, 1998 mol, 2 eq) andDMAP (dimethylaminopyridine) (7.3 kg, 60 mol, 0.06 eq). The mixture wasstirred 32 hours at 30° C. TLC showed complete conversion (sample fromthe reaction mixture and standard samples for compounds 1 and 2 wereapplied to a commercial silica gel TLC plate, and the plate was run inthe mobile phase petroleum ether/ethyl acetate=4:1. Compound 2, tritylchloride, trityl alcohol and trityl methyl ether can be detected underUV₂₅₄. They can also be visualized using iodine treatment. The R_(f) fortrityl methyl ether was ˜0.9. The R_(f) for compound 2 was ˜0.4. TheR_(f) for trityl alcohol was ˜0.3. Compound 1 does not move on TLC plateusing this method. It can be detected using the TLC method described forExample 1a. Methanol (50 L) was added in one portion, the reaction wasstirred for another 1 hour. Half of this material was transferred toanother 2000 L reactor. The reaction mixture in each reactor was dilutedwith aqueous saturated ammonium chloride (600 L) over 0.5 hour withstirring, then with ethyl acetate (500 L). The layers were cut. Theaqueous layer in each reactor was extracted with 150 L of ethyl acetate.The combined ethyl acetate extract (about 1400 L) was introduced into a2000 L reactor, washed twice with brine (300 L) and dried 6 hours oversodium sulfate. Ethyl acetate was distilled under vacuum over 15 hours(water bath temperature <60° C.) to about 600 L volume. This residue wasused in the following chromatography. The residue from above was dividedinto 20 portions. Each portion was added to 30 kg of silica gel (100-200mesh) in a 100 L container with vigorous stirring to get an evenmixture. The silica gel with crude product was then dried in a vacuumoven over 12 hours. To a column (1500 mm, φ400 mm) was added 4 kg ofsilica gel (200-300 mesh). On the top was added 2.5 kg of silica gelwith crude product. Fifteen such columns were run at the same time andmonitored by TLC. The column was first washed with petroleum ether/ethylacetate/dichloromethane=10:1:1 (60 L), then changed to petroleumether/ethyl acetate/dichloromethane=5:1:1. These fifteen columns usuallytook three to five hours to complete. The eluates were monitored by TLC.Eluates with compound 2 as major component were combined. The combinedeluate was concentrated in a 300 L reactor to ˜50 L under vacuum (waterbath not exceeding 60° C.). The set of the fifteen columns was carriedout 34 times for this batch. The concentrated eluates were combined andfurther concentrated to about 200 L under vacuum in a 500 L reactor(water batch not exceeding 60° C.). To the residue was added 100 L oftoluene, and the mixture was distilled under vacuum to near dryness toremove residue water (water bath at 60° C.). Another 100 L of toluenewas added, and the distillation was repeated. Altogether 115 kg ofcompound 2 was obtained. ¹H-NMR (300 MHz, CDCl₃), δ 7.21-7.40 (m, 15H),5.72 (d, J=4.0 Hz, 0.4H), 5.32 (s, 0.6H), 4.76 (d, J=5.6 Hz, 0.6H), 4.72(dd, J=6.0, 4.0 Hz, 0.4H), 4.63 (d, J=6.0 Hz, 0.6H), 4.57 (dd, J=6.4,1.2 Hz, 0.4H), 4.33 (m, 0.6H), 4.17 (m, 0.4H), 4.09 (bs, 2H), 3.40 (dd,J=10.4, 2.8 Hz, 0.4H), 3.39 (dd, J=10.0, 3.6 Hz, 0.6H), 3.32 (dd,J=10.0, 3.6 Hz, 0.6H), 3.00 (dd, J=10.4, 3.2 Hz, 0.4H), 1.53 (s, 1.2H),1.46 (s, 1.8H), 1.35 (s, 1.2H), 1.32 (s, 1.8H).

Example 2b

To compound 1 (almost 120 kg) and 1590 kg DCM was added 152 kg of tritylchloride at −5 to −10° C. under nitrogen atm. in a 2000 L reactor and asolution of TEA (triethylamine) (71 kg) and DMAP (2.88 kg) in DCM 175 kgwas slowly added. The reaction mixture was stirred at −5 to −10° C. for32 hr and warmed to 15-20° C. (4° C./h) and kept at 15-20° C. for 12 hafter which time LC-MS showed trityl chloride <2%. The reaction wasquenched by 20 kg water, the organic phase was separated, dried andconcentrated to a residue, and MTBE (methyl tert-butyl ether) (500 kg)was added, with stirring to result in a clear solution. Water (600 kg)was added, and the mixture was stirred for 3 h, then 500 kg heptane wasadded, cooled to −5° C.-0° C. and stirred for 3 h. A small amount ofyellow solid precipitated, filtered by a centrifuge. Then the organiclayer washed with saturated NH₄Cl solution (600 kg), pH was adjustedwith 0.5 N aqueous citric acid to pH=3-4, and the organic layercollected, dried with Na₂SO₄, filtered and concentrated under vacuum toget crude compound (2),(3aR,6aR)-2,2-dimethyl-6-((trityloxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-ol,as oil. This crude (2) (228.5 kg) was purified by silica gel column(1.0× of silica gel was used to pre-absorb the crude material, 2.3× ofsilica gel was used to pack the column), eluted by the solvent (EA(ethylacetate):PE(petroleum ether)=1:8), to get 93 kg (four batches) of (2)dispersed in toluene (assay by HPLC).

Example 3a1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol(3)

Into a 20 L reactor was charged triphenylphosphine (2.55 kg, 9.72 mol,2.1 eq) and iodoform (3.83 kg, 9.72 mol, 2.1 eq), followed by toluene (8L). The stirred solution was cooled down to −20° C. in dry ice/acetonebath. Potassium tert-butoxide (1.13 kg, 9.26 mol, 2 eq) was added inportions (within ˜30 minutes) while keeping reaction temperature <10° C.The mixture turned dark and some precipitates formed. After addition,the suspension was stirred another hour at 5˜10° C. A solution ofcompound 2 (2 kg, 4.63 mol, 1 eq) in toluene (5 L) was added to thesuspension at 5° C. The reaction was quenched with brine (1.5 L) after1.5 hours. HPLC showed the ratio of 2 (6.4 min) and 3 (˜9.8 min) asabout 1:3, while little or no by-product 3a (where the OH group of 3 isadded with elimination of HI onto the double bond of 2 to form(3aR,6aR)-4-(iodomethylene)-2,2-dimethyl-6-((trityloxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxole)was observed. The reaction mixture was diluted with ethyl acetate (2 L)and stirred 15 minutes to get a diluted suspension. Eight such 20 Lreactions were combined. The supernatant was decanted and centrifuged.The residue was diluted with water (40 L) and ethyl acetate (40 L). Thesuspension was stirred for 10 minutes and then centrifuged. The solidwas washed with 40 L of ethyl acetate once. The filtrate and wash werecombined. Layers were cut. The organic layer was washed with brine (30L) and water (30 L). It was then concentrated to dryness (temperature ofthe water bath <50° C.). The residue was loaded on a silica column andeluted first with petroleum ether/ethyl acetate (10:1), and then withpetroleum ether/ethyl acetate/dichloromethane (20:1:1). After thedesired product appeared, the column was washed with petroleumether/ethyl acetate/dichloromethane (5:1:1). Altogether 5.3 kg of 3 wasobtained (HPLC purity 95%, yield 21%). A sample from the reactionmixture and standard samples for compounds 2 and 3 were applied to acommercial silica gel TLC plate, and the plate was run in petroleumether/ethyl acetate=4:1. Compounds 2, 3 and 3a can be detected underUV₂₅₄. They can also be visualized with iodine. The R_(f) for compound 2was ˜0.4. The R_(f) for 3 was ˜0.7. The R_(f) for 3a was ˜0.9.; ¹H-NMR(300 MHz, CDCl₃), δ 7.23-7.46 (m, 15H), 7.05 (d, J=8.4 Hz, 1H), 4.53(dd, J=5.7, 8.4 Hz, 1H), 4.19 (dd, j=5.7, 8.4 Hz, 1H), 3.67 (m, 1H),3.32 (d, J=4.8 Hz, 1H), 2.46 (d, J=4.8 Hz, 1H), 1.34 (s, 3H), 1.33 (s,3H); ¹³C-NMR (75 MHz, CDCl₃) δ147.65 (−CH═CI₂), 143.75, 128.68, 128.00,127.29, 127.23, 109.55, 86.97, 83.39, 77.21, 69.19, 27.84, 25.52, 15.99(═CI₂).

Example 3b

To a 1000 L flask was added toluene (344 kg) and THF (110 kg) under N₂flushing. Iodoform (58.4 kg) was added and stirred at room temperaturefor 10 min to give a homogeneous solution to which molecular sieves (50kg) were added, and the mixture was stirred for 13 h (water content was110 ppm by KF), after which molecular sieves were filtered and PPh₃(37.2 kg) was added and the mixture was stirred at 10° C. for 30 min andcooled to 0-5° C. Then t-BuOK (15.6 kg) was added in a few portions,during which the temperature was kept as <15° C. resulting in asuspension which was stirred at 25° C. for 10 h. 2 (28 kg) solution in80 kg toluene (KF: no water was detected) was added drop wise into theWittig mixture and the mixture stirred for 3 h at 10° C. IPC (in processcontrol) by HPLC showed ˜5.5% 2 was left). 2.0 kg water was added toquench the reaction and after 30 min, Na₂SO₄ (50 kg) was added andstirred for 3 h. Then the solid was filtered, cake was slurried with 100kg toluene and the solid filtered. The organic layers were combined(HPLC assay showed about 23.07 kg 3 in the organic layer), dried andcooled to 0-10° C. and the solution was used in the next oxidation stepwithout further purification.

Example 4a1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone(4)

Compound 3 (38 kg, 55.7 mol) was dissolved in 100 L of dichloromethaneand the solution was added into a 1000 L reactor charged withdichloromethane (500 L) followed by addition of 4 Å molecular sieves(42.9 kg) and neutral alumina (84 kg). To the stirred suspension atambient temperature was added PDC (pyridinium dichromate) (25.1 kg, 66.8mol) and the mixture was stirred 16 hours, until HPLC indicated completeconversion. The suspension was filtered using a centrifuge. The filtratefrom the centrifuge was collected. The cake from the centrifuge (mainlyalumina, molecular sieves and PDC residue) was washed with 2×100 L ofmethyl tert-butyl ether. The combined filtrate and wash was introducedinto a 1000 L reactor and concentrated to dryness while keeping theheating below 50° C. To the residue was added 600 L of methyl tert-butylether, followed by 5 kg of activated carbon. The dark suspension washeated 1 hour at 60° C., then cooled down to 30° C. It was filteredthrough a pad of Celite to remove activated carbon. The filtrate wasconcentrated to dryness. The oily residue was diluted with 60 L ofmethanol and precipitates started to form. The thick suspension wasstirred 1 hour at ambient temperature, then the precipitates werecollected by filtration. The cake was washed twice with 50 L ofpetroleum ether and dried at 40° C. to afford 25.3 kg of 4 (yield 67%,purity >99%) as white solid. The R_(f) for 3 was ˜0.7, while R_(f) for 4was ˜0.75 on silica gel TLC plate run in petroleum ether/ethylacetate=4:1 and visualized under UV₂₅₄ light or by using iodinetreatment. ¹H-NMR-(300 MHz, CDCl₃) δ 7.23-7.48 (m, 15H), 6.80 (d, J=7.5Hz, 1H), 4.75-4.85 (m, 2H), 3.95 (d, J=18.0 Hz, 1H), 3.80 (d, J=18.0 Hz,1H), 1.41 (s, 3H), 1.34 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ 203.22,145.93 (—CH═CI₂), 143.07, 128.62, 128.52, 128.21, 128.08, 127.43,111.01, 87.57, 82.95, 80.00, 69.10, 26.85, 25.11, 18.53 (═CI₂).

Example 4b

To the final solution in Example 3b was added DMSO (dimethyl sulfoxide)(5.2 kg), DIC (diisopropylcarbodiimide) (7.9 kg) and pyridine (7.6 kg).Then CF₃COOH (4.9 kg) was added drop-wise, keeping the temperature <20°C. (exothermic reaction) and the mixture was stirred for an hour. Thenadditional DMSO (2.6 kg), DIC (3.9 kg) and pyridine (3.8 kg) were addedfollowed by drop-wise addition of CF₃COOH (2.45 kg) at <20° C. HPLCshowed full consumption of 3. The reaction mixture was cooled to 0-5° C.NaOCl (˜7%, 108 kg,) was added slowly with stirring for 1 h after whichthe mixture was filtered, the solid was washed (2×30 kg of toluene), thelayers were separated and the organic phase was washed with water (2×200kg), brine (250 kg) and distilled under reduced pressure <65° C. to aresidue. The residue was cooled to 0-5° C., ethanol was added (120 kg)and the solution was stirred at 0° C. for 4 h resulting in a slurry. Thesolid was filtered and dried to give pure 4 (19.2 kg).

The formation of 4 from 3 can be carried out with Moffat oxidation orSwern oxidation.

Example 5a(1R,4S,5S)-2-Iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol(5)

Into a 20 L reactor was added 4 (1.5 kg, 2.2 mol) and anhydrous THF (7L). The stirred solution was cooled down to <−70° C. n-BuLi (2.5 M, 1.06L, 2.65 mol, 1.2 eq) was added drop wise to the reaction mixture at sucha rate that temperature did not exceed −65° C. It took about 1.5 hour.The reaction mixture was stirred 1 hour at below −70° C. HPLC indicatedcomplete consumption of 4. A saturated solution of ammonium chloride (1L) was added drop wise to the reaction mixture. The mixture was thenallowed to warm up to room temperature. Eight such 20 L reactions werecombined and introduced into a 300 L reactor. The mixture waspartitioned between brine (16 L) and ethyl acetate (60 L) and stirredfor 30 minutes. The layers were cut. The organic layer was washed withbrine (20 L), dried over sodium sulfate, and concentrated under vacuum(temperature <40° C.). The residue was put on a silica gel column. Thecolumn was eluted with petroleum ether/ethylacetate/dichloromethane=15:1:1. Altogether 4.09 kg of 5 were obtained(yield 42%, HPLC >95%). Sample from the reaction mixture and standardsamples for compounds 4 (R_(f)˜0.75) and 5 (R_(f)˜0.55) were run onsilica gel TLC plate in petroleum ether/ethyl acetate=4:1 visualizingwith UV₂₅₄ light and also by iodine treatment. ¹H-NMR (300 MHz, CDCl₃) δ7.31-7.62 (m, 15H), 6.50 (d, J=1.8 Hz, 1H), 5.24 (dd, J=1.8 Hz, 5.7 Hz,1H), 4.68 (d, J=5.7 Hz, 1H), 3.69 (d, J=9.0 Hz, 1H), 3.36 (s, 1H, OH),3.27 (d, J=9.0 Hz, 1H), 1.46 (s, 3H), 1.36 (s, 3H); ¹³C-NMR (75 MHz,CDCl₃) δ 144.23 (—CH═CI—), 143.53, 128.89, 127.95, 127.29, 112.44,104.99 (═CI—), 87.64, 85.66, 84.40, 83.10, 65.40, 27.45, 26.62.

Example 5b

Compound 4 (29.0 kg) was dissolved in THF (220.0 kg, 247 L, KF: 190 ppm)and cooled to −75° C. n-BuLi (17.8 kg, 1.15 eq) was added at temperaturebelow −70° C. over 3 hrs., then the mixture was stirred at −70±2° C. for3 hrs. after which time HPLC indicated almost complete consumption of 4(5.9% area remained) and formation of 5. Therefore, the reaction mixturewarmed slowly to −40° C. over 1.5 hrs followed by slow and continuouswarming of the reaction mixture to −25° C. over 1.5 hrs to result inonly 1.1% of 4. The reaction was added to saturated NH₄Cl (15 kg) in 1h, the mixture was kept at −7±2° C. while quenching. Then the mixturewas extracted with EA (4.5 kg×2). The EA phase (23 kg) was dried overNa₂SO₄ then concentrated in vacuum at 40° C. in −0.08 MPa for about 5hrs. The residue was dissolved in DCM (10.1 kg) to afford solution of 5(10.7 kg) which was used in the next oxidation step.

This reaction from 4 to 5 is a general reaction, which is, for example,useful for forming carbocyclic compounds. This reaction has notpreviously been reported. For example, this reaction can be used withother reactants and products.

Example 6a3aR,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one(6)

Into a 100 L reactor was added a solution of 5 (5.54 kg, 10 mol) indichloromethane (50 L), followed by 4 Å molecular sieves (8.3 kg) andneutral alumina (16.6 kg) and PDC (12.03 kg, 32 mol). The suspension wasstirred for 12 hours at ambient temperature. HPLC indicated completeconversion. The suspension was centrifuged. The cake was washed withmethyl tert-butyl ether (2×50 L). The combined filtrate and wash wasintroduced into a 200 L reactor and concentrated under vacuum to dryness(heating temperature kept <50° C.). To the residue was added 100 L ofmethyl tert-butyl ether, followed by 0.5 kg of activated carbon. Thedark suspension was heated for 1 hour at 60° C. and then cooled down to30° C. and then filtered through a pad of Celite. The filtrate wasconcentrated to dryness. The residue was diluted with 6 L of methanol.The thick suspension was stirred 2 hours at ambient temperature and thenfiltered. The cake was washed twice with 5 L of petroleum ether, anddried in a vacuum oven (<40° C.) to afford 2.94 kg of 6 (yield 53%, HPLC˜99%) as a white solid. Sample from the reaction mixture and standardsamples for compounds 5 and 6 were applied to a commercial silica gelTLC plate which was run in petroleum ether/ethyl acetate=4:1 andvisualized under UV₂₅₄ and/or using iodine treatment. The R_(f) for 5was ˜0.55 while the R_(f) for compound 6 was ˜0.57. ¹H-NMR (300 MHz,CDCl₃) δ 7.15-7.53 (m, 15H), 5.44 (d, J=5.7 Hz, 1H), 4.32 (d, J=5.7 Hz,1H), 4.30 (d, J=15.6 Hz, 1H), 4.18 (d, J=15.6 Hz, 1H), 1.45 (s, 3H),1.32 (s, 3H); ¹³C-NMR DEPT-135 (75 MHz, CDCl₃) δ 128.73, 128.11, 127.45,79.34, 74.9, 64.33 (OCH₂—), 27.4, 26.81.

Example 6b

Solution of 5 in DCM was added to reactor, then PDC (1800 g) andmolecular sieves (362 g) were added and the mixture stirred and warmedto 25° C. Ac₂O (274 g) was added at 25° C. over 0.5 h, and then stirredfor 30 min. The mixture reached 36° C. in 10 min. then cooled to 25° C.and stirred for 1.5 hrs, until IPC showed full consumption of 5. Thesuspension filtered through silica (1.37 kg) pad and the filtrate waswashed with brine (3.69 kg) and the organic phase concentrated in vacuumat 15±5° C. The residue was dissolved in MTBE (4.4 kg), active carbon(0.05 kg) was added and the suspension stirred for 2 hrs. Then filteredto afford solution of 6 in MTBE (4.84 kg) ready to use in the nextreduction step.

Example 6c

Compound 5 (72.5 g, 130.7 mmol) was taken up in methylene chloride (725mL, 10 V) and charged to a 2 L three-neck flask equipped with anoverhead stirrer, a nitrogen inlet, a thermocouple, and molecular sieves(72.5 g). Acetic anhydride (24.7 mL, 2.0 eq) was added followed bypyridinium dichromate (54.1 g, 143.8 mmol, 1.1 eq). The reaction wasstirred at room temperature for 3 h. The reaction mixture was filteredthrough 350 g silica gel. The dark-colored chromium salts remained onthe silica plug. The silica plug was washed with 200 mL methylenechloride. The resulting filtrate was washed with saturated sodiumbicarbonate solution (200 mL), and then washed with 200 mL saturatedsodium thiosulfate. The color was removed. The organic layer wasconcentrated to an orange oil to afford compound 6. Approximately 72 gof crude material was collected in 59 A % purity.

Example 7a(3aS,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(7)

Into a 500 L reactor was charged 100 L of methanol, followed by additionof 6 (9.7 kg) and CeCl₃-7H₂O (7.2 kg) in 1 kg portions over 0.5 hour.Temperature of the reaction mixture rose ˜5° C. during the addition. Thereaction mixture was cooled down to −10° C., and NaBH₄ (0.77 kg) wasadded in portions (˜150 g) over 1 hour resulting in strong H₂ evolutionwith elevation of the reaction temperature. The transparent reactionmixture was then stirred for 2 hours at 0° C. until HPLC indicatedcomplete conversion. Then 150 L of brine were added to result in whiteprecipitates. The suspension was concentrated under vacuum to removemost of methanol and ethyl acetate (100 L) was added to the resultingresidue and the mixture was stirred for 30 minutes. Then the organiclayer was separated washed with brine (20 L) and dried over sodiumsulfate, filtered and concentrated to dryness, and the residue was useddirectly in the next step. Sample from the reaction mixture and standardsamples for compounds 6 and 7 were applied to a commercial silica gelTLC plate, with petroleum ether/ethyl acetate=4:1 as the mobile phase. 6and 7 can be detected under UV₂₅₄ or visualized using iodine treatment.The R_(f) for 6 was ˜0.55 while the R_(f) for compound 7 was ˜0.57;¹H-NMR (300 MHz, CDCl₃) δ 7.21-7.48 (m, 15H), 5.20 (d, J=5.7 Hz, 1H),4.77 (t, J=5.7 Hz, 1H), 4.39 (dd, J=5.4, 11.2 Hz, 1H), 3.90 (d, J=12.0Hz, 1H), 3.79 (d, J=12.0 Hz, 1H), 2.81 (d, J=11.2 Hz, 1H), 1.43 (s, 3H),1.32 (s, 3H); ¹³C-NMR DEPT-135 (75 MHz, CDCl₃) δ 128.79, 127.89, 127.11,82.91, 78.14, 76.48, 62.58 (OCH₂—), 27.54, 27.11.

Example 7b

A solution of compound 6 (from Example 6b) was added to the reactor andcooled to 0° C. 2.2 kg MeOH was added followed by addition of CeCl₃.7H₂O(355 g) and the mixture stirred for 1 h to result homogeneous solution.NaBH₄ (8.8 g) was added in portions at 0° C., stirred for 30 min, IPCshowed the reaction started and additional NaBH₄ (30 g) was added inportions with stirring for 1 h at 0° C. IPC showed complete consumptionof compound 6. Saturated NH₄Cl (0.27 kg) was added followed by celite(266 g) and the mixture stirred for 30 min after which it was filtered,washed with water (12 L×3), and dried over Na₂SO₄ to give compound 7 inMTBE solution (5.5 kg), which was concentrated (below 40° C.) to furnisha residue. DMF (3 kg) was added and the solution was used directly inthe next step.

Example 8aTert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(8)

Into a 500 L reactor was charged DMF (100 L), Imidazole (3.6 kg) andcrude compound 7 (from Example 7a, ˜9.7 kg). The mixture was stirred atambient temperature under nitrogen and t-BDPSCl (tert-butyldiphenylchlorosilane) (1 kg) was added in portions over 1 hour. The reactionmixture was stirred 18 hours at ambient temperature. HPLC indicatedcomplete conversion. Into the reactor was charged brine (100 L) andethyl acetate (100 L) and the mixture was stirred for 30 minutes. Theorganic phase separated and the aqueous layer was extracted twice with50 L of ethyl acetate. The combined ethyl acetate extract was washedtwice with water (30 L) and concentrated under vacuum to give agolden-colored residue (˜15.2 kg). The residue was diluted with 20 L ofmethanol and the mixture was stirred 1 hour at ambient temperature. Thewhite precipitates were collected by filtration and dried in a vacuumoven (<40° C.) to afford compound 8 (8.3 kg, yield 60%, purity ˜99%) asa white solid. Sample from the reaction mixture and standard samples forcompounds 7 and 8 were applied to a commercial silica gel TLC plate, andthe plate was developed in the mobile phase petroleum ether/ethylacetate=10:1. Compounds 7 and 8 can be detected under UV₂₅₄. They canalso be visualized using iodine treatment. The R_(f) for 7 was ˜0.1. TheR_(f) for compound 8 was ˜0.9, ¹H-NMR (300 MHz, CDCl₃) δ 7.18-7.82 (m,25H), 4.94 (d, J=5.6 Hz, 1H), 4.47 (d, J=5.6 Hz, 1H), 4.05 (t, J=5.6 Hz,1H), 3.89 (d, J=12.0 Hz, 1H), 3.78 (d, J=12.0 Hz, 1H), 1.29 (s, 3H),1.26 (s, 3H), 1.13 (s, 9H); ¹³C-NMR DEPT-135 (75 MHz, CDCl₃, δ<100) β82.68, 78.96, 76.63, 62.78, 27.50, 27.11.

Example 8b

Imidazole (133.6 g) was added to solution of compound 7 (from Example7b, KF:0.14%) and t-BDPSCl (448.5 g) was added drop-wise at 20-25° C.and the mixture was stirred for 14 hrs after which time it was addeddrop wise into 12 kg of water below 25° C. then stirred for 30 min.Ethyl acetate (5.8 kg) was added, the organic phase separated and theaqueous layer was extracted with ethyl acetate (2.9 kg×2). The combinedorganic phase was washed with brine (2.9 kg×2), dried and thenconcentrated below 45° C. EtOH (600 g) was added and the mixture washeated to 30° C. to give a solution from which a solid precipitated outwithin 10 min. The mixture was stirred at 15° C. for 2 hrs and the solidfiltered. The cake was washed with EtOH (50 g×2) to give a white solidwhich was dried in vacuum at 45° C. for 20 hrs to give 400 g of compound8.

Example 9aTert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(9)

Compound 8 (0.48 kg) and NFSI (N-fluorobenzenesulfonimide) (0.29 kg) wasdissolved in Ulf (3 L) and ether (1 L). To the solution was added 1.5 Lof n-pentane, and the mixture was cooled to −78° C. in a dry-ice bath. Asolution of n-BuLi in THF (2.5 M, 0.72 L) was added drop wise to thereaction mixture within 4 hours, while keeping the reaction temperaturebelow −70° C. The reaction mixture was stirred another hour until HPLCindicated complete consumption of compound 8. Saturated ammoniumchloride solution (aqueous, 2 L) was added drop wise to the reactionmixture. It was then allowed to warm to ambient temperature. Eight suchreactions were combined and diluted with 30 L of ethyl acetate. Themixture was stirred for 30 minutes, then the organic phase separated andthe aqueous layer was extracted with 20 L of ethyl acetate. The combinedorganic phase was washed with brine (10 L), dried over sodium sulfate,and concentrated to dryness. HPLC indicated ratio of compound 9 to itscorresponding de-fluoro side product was about 3/1. The residue wasloaded on a silica gel column (300˜400 mesh) and eluted with petroleumether/dichloromethane/ethyl acetate (first 100/0/0, then 200/10/1 toremove the front impurities, then changed to 200/15/1 to collect thedesired product 9, (then 200/20/1 to collect the side product).Altogether 1.38 kg of compound 9 (yield 36%, purity=95%) was obtained.¹H-NMR (300 MHz, CDCl₃) δ 7.25-7.92 (m, 25H), 5.04 (t, J=7.2 Hz, 1H),4.45 (m, 1H), 4.33 (m, 1H), 3.98 (d, J=12.0 Hz, 1H), 3.86 (d, J=12.0 Hz,1H), 1.55 (s, 3H), 1.48 (s, 3H), 1.18 (s, 9H); ¹³C-NMR DEPT-135 (75 MHz,CDCl₃, δ<100) β 78.70, 75.35, 71.10, 56.39, 28.04, 27.25, 26.82.

Example 9b

Compound 8 (1.53 kg) and NFSI (1.64 kg) were dissolved in a mixture ofTHF/Hexane/MTBE and the mixture was stirred at room temperature for 5minutes to form a clear solution. Then the solution was cooled to −65°C. with dry-ice bath (in acetone) under N₂ atmosphere. More solidsprecipitated during the cooling down and the solution became turbid. At˜−65° C., n-BuLi was added drop wise into the mixture. The reactiontemperature needed strict monitoring and was kept at −55˜65° C. Theaddition of n-BuLi lasted for 4 h. (During the addition of n-BuLi (about40% of the amount), a large amount of solid precipitated. That blockedthe stirring.) After the addition of n-BuLi, the solution was stirred atabout −60° C. for 0.5 h. TLC and HPLC showed complete consumption ofcompound 8. The solution was quenched with sat. NH₄Cl (3 L), then thedry-ice bath was removed. Water (6 L) was added slowly to the mixture,which was stirred at room temperature for 30 minutes. Then the solutionwas allowed to stand for 15 minutes to separate into two layers. Theorganic layer was separated (10.3 kg). The aqueous layer was extractedwith ethyl acetate (1.8 kg×1). Five such reactions were combined and thecombined organic phase of the five batches were washed with brine, anddried over Na₂SO₄ (55 kg total based on Assay the product weight was 3.4kg). Silica gel (300-400 mesh, 8 kg, 1.3 eq. (based on 8, wt./wt.)) andTEA (0.003 eq. (based on silica gel, wt./wt.)) were added to the crudeproduct (about 8 kg) solution and the mixture was evaporated to drynessat ˜35° C. and was loaded on a column (diameter: 45 cm; height: ˜130 cm;silica gel: 300-400 mesh, 60 kg, 10 eq. (based on 8, wt./wt.); TEA:0.003 eq. (based on silica gel, wt./wt.); eluent: PE/EA=200/1-150/1).During column chromatography, the fractions (plastic buckets (5 L)) werestrictly monitored by TLC/HPLC. According to TLC/HPLC data, differentparts were collected and concentrated respectively. The resulting solidsfrom chromatography with different purity were slurried with heptane (3v, stirred at 20-25° C. for 0.5 h) first to remove some of low polarityimpurities, and then recrystallized with 6.6 v of iPrOH/heptane (10/1,v/v). The mixed solvent was added to crude solid product, and themixture was heated at 85° C. to refluxing until the solid dissolvedcompletely, then the heating bath was removed, the solution was cooledto 20-25° C. automatically under stirring, and was stirred for another1-2 h at this temperature. The resulting solid was filtered andmonitored by HPLC. Normally 2-3 (or more) recrystallizations were neededto reach purity of ≧97.0% of 9 and des-fluoro impurity <0.5% area (byHPLC, note: the recrystallization was effective to minimize des-fluoroimpurity)).

Example 9c

Selective fluorination of compound 8 was performed through a boronicacid intermediate. Boronic acid intermediates were prepared fromcompound 8 by the following boronate reactions, Examples 9c-1 through9c-3.

Example 9c-1[(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronicacid (compound 9c-1)

To a 100 mL round-bottom 3-neck flask equipped with nitrogeninlet/outlet, stir bar, and thermocouple with temperature controller wascharged 3.0877 g of compound 8 (3 mmol, 1.0 eq) and 30 mLtetrahydrofuran (10 V). Reaction was cooled to 0° C. To this solutionwas added 6.98 mL (9 mmol, 2.4 eq) of isopropylmagnesium chloridelithium chloride complex, 1.3 M in THF slowly over 15 minutes. Thereaction was stirred at 0° C. for 1 hour. An HPLC assay indicated theformation of intermediate. 1.05 mL of trimethylborate (9 mmol, 2.5 eq)was added to the reaction. An HPLC assay after 1 hour at 0° C. indicatedthat the reaction was completed. Quenched reaction with saturatedaqueous ammonium chloride solution (3V). The ice bath was removed andthe reaction was warmed to room temperature. The reaction was chargedwith DI water (3V) and ethyl acetate (6V). The layers were separated andthe aqueous layer was back-extracted with ethyl acetate (6V). Theorganic phases were combined and washed with brine (3V) and dried overMgSO₄. The resulting mixture was filtered. The filtrate was concentratedto dryness with a rotary evaporator. Obtained 2.87 grams (100% crudeyield), 96 A % purity of [(3 aR, 6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronicacid (compound 9c-1).

Example 9c-2 [(3aR,6S,6aR)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy-tert-butyl-diphenyl-silane (9c-2)

To a 25 mL round-bottom 3-neck flask equipped with nitrogeninlet/outlet, stir bar, and thermocouple with temperature controller wascharged 0.2806 g of compound 8 (0.353 mmol, 1.0 eq) and 3 mLtetrahydrofuran (10 V). The reaction was cooled to 0° C. To thissolution was added 0.653 mL (0.847 mmol, 2.4 eq) of isopropylmagnesiumchloride lithium chloride complex, 1.3 M in THF slowly over 15 minutes.The reaction was stirred at 0° C. for 1 hour. HPLC assay indicatedformation of intermediate. 0.128 mL of 4,4,5,5 tetramethyl-1,3,2dioxaborolane (0.884 mmol, 2.5 eq) was added to the reaction. An HPLCassay after 1 hour at 0° C. indicated that the reaction was completed.The reaction was quenched with saturated aqueous ammonium chloridesolution (3V). The ice bath was removed and the reaction warmed to roomtemperature. The reaction was charged with DI water (3V) and ethylacetate (6V). The layers were separated and the aqueous layer wasback-extracted with ethyl acetate (6V). The organic phases were combinedand washed with brine (3V) and dried over MgSO₄. The resulting mixturewas filtered. The filtrate was concentrated to dryness by the rotaryevaporator. Obtained 0.098 grams as a white solid, (35% yield), 80 A %purity of[(3aR,6S,6aR)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy-tert-butyl-diphenyl-silane(compound 9c-2).

Example 9c-3[(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronicacid (9c-1) using ligand

To a 100 mL round-bottom 3-neck flask equipped with nitrogeninlet/outlet, stir bar, and thermocouple with temperature controller wascharged 0.2272 g of compound 8 (0.286 mmol, 1.0 eq) and 3 mLtetrahydrofuran (THF). The reaction was cooled to 0° C. To this solutionwas added 0.528 mL (0.686 mmol, 2.4 eq) of isopropylmagnesium chloridelithium chloride complex, 1.3 M in THF slowly over 15 minutes. Thereaction was stirred at 0° C. for 1 hour. Added 0.065 mL (0.343 mmol,1.2 eq) of Bis[2-(N,N-dimethylamino)ethyl]ether. An HPLC assay indicatedthe formation of intermediate. 1.05 mL of trimethylborate (0.009 mmol,2.5 eq) was added to the reaction. The ice bath was removed and thereaction allowed to warm to room temperature for 30 minutes. An HPLCassay indicated that the reaction was complete. The reaction was cooledto 0° C. The reaction was quenched with saturated aqueous ammoniumchloride solution (3V) The ice bath was removed and the reaction waswarmed to room temperature. The reaction was charged with DI water (3V)and ethyl acetate (6V). The layers were separated and the aqueous layerwas back-extracted with ethyl acetate (6V). The organic phases werecombined and washed with brine (3V) and dried over MgSO₄. The resultingmixture was filtered. The filtrate was concentrated to dryness with arotary evaporator. Obtained 0.077 grams as a white solid, (36% yield),and 100 A % purity of [(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronicacid (compound 9c-1).

Example 9c-4[(3aR,6R,6aR)-5-fluoro-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy-tert-butyl-diphenyl-silane(compound 9)

To a 100 mL round bottom flask equipped with nitrogen inlet/outlet, stirbar, and thermocouple with temperature controller was charged 2.877grams of boronic acid intermediate (for example, either compound 9c-1 orcompound 9c-2) (3.89 mmol, 1.0 eq) in methyl-tert-butyl ether (6 V). Ina separate flask was charged 0.186 grams sodium hydroxide flakes (4.67mmol, 1.2 eq) and methanol (10V), The solution was stirred until all thesodium hydroxide went into solution. The sodium hydroxide/methanolsolution was added to the boronic acid intermediate and the reaction wasstirred at room temperature for 15 minutes. After 15 minutes thereaction was cooled to 0° C. 3.012 grams of silver trifluoromethanesulfonate (11.67 mmol, 3.0 eq) was added in one portion. The reactionturned brown. After 30 minutes HPLC showed all the starting boronic acidintermediate was consumed. The solvent was removed with a rotaryevaporator using no heat on the water bath. Any residual methanol wascoevaporated with acetone (2×5 V). Acetone (10 V) was added to the cruderesidue. 7.042 grams of 4 Å molecular sieves (2.5 wt) and 4.2312 gramsof 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (Selectfluor®) (4.67 mmol, 3.0 eq) was added tothe reaction. The reaction was stirred at room temperature for 1 hour.HPLC showed that the reaction was completed. The reaction was filteredthrough Celite® and concentrated on the rotary evaporator to obtain 2.07grams (78% yield) of compound 9 as a white solid.

Example 10(3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(10)

Compound 9 (1370 g, 1 wt, 1 eq) was dissolved in THF (5.5 L, 4 vol).TBAF (tetra-n-butylammonium fluoride) 1.0 M in THF (2.20 L, 1.61 vol)was added in one portion (not exothermic) and the resulting solutionstirred at 20 to 25° C. After 2 h, TLC analysis (70:30 heptanes:TBME(methyl tert-butyl ether) 7:3, KMnO₄ visualisation) indicated thereaction was complete by absence of starting material. The reactionmixture was concentrated to an oil under reduced pressure at 40° C.(water bath) on a rotary evaporator until solvent collection ceased. Theresidue was dissolved in TBME (11.0 L, 8 vol) and subsequently washedwith water (2×4.1 L, 2×3 vol) and saturated sodium hydrogen carbonate(4.1 L, 3 vol). The organic phase was dried over Na₂SO₄ (1.37 kg, 1 wt),filtered and the cake washed with TBME (1.37 L×2,2×1 vol). The combinedfiltrates were concentrated under reduced pressure at up to 40° C.(water bath) on a rotary evaporator until the TBME content was <5% w/wby ¹H NMR to give 10 as a thick pale yellow/orange oil. ¹H-NMR (400 MHz,CDCl₃) δ 7.7 ppm (d, 4H) TBDPS-F, 7.2-7.5 ppm, (m, 21H) Trityl andTBDPS-F, 5.1 ppm, (t, J=6.3 Hz, 1H) (CH), 4.7 ppm, (m, J=3.5 Hz, 1H)(CH), 4.4 ppm, broad (t, 6.3 Hz, 1H) (CH), 3.9 ppm, (d, J=11.9 Hz) 1H,3.8 ppm, (d, J=9.9 Hz, 1.7 Hz, 1H) (CH₂), δ 2.8 ppm, (d, J=9.4 Hz, 1H)(OH), δ1.48 ppm, s, 3H CH₃ Acetonide, δ1.46 ppm, s, 3H CH₃ Acetonide, δ1.1 pm, s, 9H TBDPS-F (3×CH₃), Solvents δ 3.2 ppm, 1.2 ppm TBME, δ 3.7ppm, 1.7 ppm THF.

Example 11(3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (11)

Compound 10 (787 g (corrected), 1 wt), (gross input 1292 g), wasdissolved in DCM (7.87 L, 10 vol) and cooled to 0 to 5° C. Triethylamine(368 mL, 0.468 vol, 1.5 eq) was charged followed by MsCl (164 mL, 0.208vol, 1.3 eq) whilst maintaining the temperature at 0 to 5° C. IPC by ¹HNMR analysis after 30 minutes indicated that 94.2% conversion had beenachieved. An additional charge of triethylamine (28 mL) and MsCl (16 mL)(2 mol % per 1% conversion remaining) was made. IPC analysis after 30minutes indicated that the conversion had increased to 97.3%. A secondadditional charge of triethylamine (13 mL) and MsCl (7.5 mL) was made.After a further 30 minutes IPC by ¹H NMR analysis indicated that 100%conversion had been achieved. Water (7.87 L, 10 vol) was charged to thereaction and the mixture warmed to 15 to 25° C. Once the reaction waswithin the temperature range it was stirred for 10 minutes and thephases separated. The organic phase was returned to the flask, saturatedNaHCO₃ (7.87 L, 10 vol) charged and the two phases mixed for 10 to 20minutes, then separated. The organic phase was dried over Na₂SO₄ (787 g,1 wt) for 10 minutes, filtered and the filter cake washed with DCM(2×787 mL, 2×1 vol). The combined filtrate and washes were concentratedat up to 30° C. on a rotary evaporator under vacuum to obtain 11 as anorange oil. ¹H-NMR (400 MHz, CDCl₃) β 7.7 ppm, d, 4H, TBDPS-F stage 1by-product, δ 7.25 to 7.5 ppm, 21H. Trityl group and TBDPS-F by-product,δ 5.23 ppm, (d, J=5.8 Hz, 1H) (CH), δ 5.10 ppm, (t, J=7.1 Hz, 1H) (CH),δ 4.77 ppm, (m, J=2.8 Hz, 1H) (CH), δ 4.0 ppm, (d, J=12.6 Hz, 1H), 3.9ppm, (d, J=12.6 Hz, 1H) (CH₂), δ 3.1 ppm, s, 3H, Mesylate, (CH₃), δ 1.4ppm, 6H, Acetonide, (2×CH₃), δ 1.1 ppm, 3, 9H, (3×CH₃, TBDPSF), Solventsδ 5.8 ppm, s, 2H DCM.

Example 124-amino-1-((3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one(12)

Cytosine (47.9 g, 0.42 wt, 2 eq) and cesium carbonate (141.4 g, 1.24 wt,2 eq) were suspended in DMSO (684 mL, 6 vol) and heated to 40 to 45° C.After 75 minutes 11 (114 g, 1 wt, corrected, 1 eq) dissolved in DMSO(400 mL, 3.5 vol) was charged to the reaction followed by a line rinseof DMSO (57 mL, 0.5 vol) and the reaction temperature adjusted to 40 to45° C. The temperature was maintained at the upper end of thetemperature range at 44 to 45° C. for the duration of the reaction.Conversion by HPLC after 4 h was 60.9% increasing to 97.6% after 20 hand a pass result obtained of 99.0% after 23 h. The ratio of the N- toO-isomers was at 88:12. The reaction was cooled to room temperature andEtOAc (1140 mL, 10 vol) charged followed by water (1140 mL, 10 vol)maintaining the temperature below at 25° C. (water addition isexothermic). After stirring for 10 minutes the phases were allowed tosettle for 10 minutes and then separated. The aqueous phase wasre-extracted with EtOAc (1140 mL, 10 vol) by stirring for 10 minutes andagain allowing too settle for 10 minutes before separating. The aqueousphase was checked by TLC and HPLC for product content, which indicatedthat all the product had been recovered with the first two extracts. Theorganic extracts were combined. 3% w/w brine (3×570 mL, 3×5 vol) washeswere performed mixing the organic extracts for 10 minutes and allowing aminimum 10 minutes for the phases to settle on ceasing prior to theseparation. Analysis of each aqueous phase by HPLC indicated that verylittle/no product was being lost. A fourth wash was performed with water(5 vol). In each case the aqueous wash was very slightly hazy inappearance. After completion of the wash sequence the DMSO level hasbeen reduced to 0.02% w/w vs. the N-alkyl product, below the targeted0.15% w/w limit. The organic phase was dried over sodium sulfate (114 g,1 wt) filtered and the filter cake washed with EtOAc (2×1 vol). Thefiltrates were concentrated at up to 40° C. (water bath) on a rotaryevaporator to give crude 12 as an orange foam 175.1 g. ¹H NMR analysisgave the following composition: 12 56.4% w/w, O-alkyl side product 7.2%w/w, t-BDPSF (t-butyldiphenylsilylfluoride) 31.3% w/w and EtOAc 5.1%w/w, which equated to an approximate contained mass of 12 of 98 g. Thecrude material was purified by dry flash chromatography on silica (1.7kg, 10 wt), complete separation of the isomers was obtained. The productfractions were concentrated at up to 40° C. (water bath) to give 12 as apale brown foam 90.5 g, 77.2% th (corrected by ¹H NMR assay). Thechemical purity by HPLC was 97.8% area. The chromatography was performedusing 4 dry flash columns per batch of crude material (4×˜170 g) eachusing 1.7 kg (10 wt) of silica. The crude product was loaded inapproximately 1 vol of DCM and then eluted using the gradient: 1×DCM,9×1% MeOH/DCM, 10×2% MeOH/DCM, 10×6% MeOH/DCM. Clean separation of thestage 1 by-product and O-alkyl isomer from 12 was achieved. The productfractions were concentrated on a rotary evaporator at up to 40° C. toobtain an orange foam. Concentration was continued until the DCM contentwas <10% w/w. ¹H-NMR (400 MHz, CDCl₃), δ 8.7 ppm, s broad, 1H, δ 7.2 to7.5 ppm, m, 16H, δ 6.7 ppm, (d, J=7.3 Hz, 1H) (CH), δ 6.6 ppm, broad s,1H, δ 5.5 ppm, (d, J=7.4 Hz, 1H) (CH), δ 5.4 ppm, (t, J=5.6 Hz, 1H)(CH), δ 4.9 ppm, broad s, 1H, (CH), δ 4.7 ppm, broad s, 1H, (CH), δ 3.9ppm, (d, J=12.1 Hz, 1H), 3.8 ppm, (d, J=12.1 Hz, 1H) (CH₂), δ 1.48 ppm,s, 3H (CH₃), δ 1.41 ppm, s, 3H (CH₃), Solvents δ 5.3 ppm, s, 2H DCM.

This reaction from 11 to 12 is a general reaction, forming 12 with highregio- and stereoselectivity, which is, for example, useful for couplingcytosine and other nucleotide bases. This reaction has not previouslybeen reported. For example, this reaction can be used with otherreactants and products.

Example 134-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)cyclopent-2-en-1-yl)pyrimidin-2(1H)-one(13)

Compound 12 (720 g, 1 wt) was charged to a flask followed by methanol(3.6 L, 5.0 vol) which formed a suspension. 2 M HCl (734 mL, 1.02 vol,1.1 eq) was added which gave a hazy solution. The mixture was heated toreflux (68 to 69° C.), after 1 h IPC by 1H NMR indicated that the trityldeprotection was complete and that removal of the acetonide had reached89%. Distillation was started and the distillate collected in 1 volumeportions. After the removal of 1 volume of distillate, 1 volume of 95:5methanol:water was added. Each distillation required 40 to 50 minutes tocomplete. After 2 cycles 97.5% conversion was achieved. After a further3 distillation cycles conversion by HPLC was 99.6%; one furtherdistillation was performed which increased the conversion to 99.8%. Theoverall reaction time was 5.5 h. The reaction was allowed to cool, thetrityl by-product, whilst initially forming an oil, crystallised oncethe temperature reached ˜40° C., the slurry was allowed to cool to roomtemperature overnight. The slurry was filtered and washed with water(2×1 vol), the combined filtrates were concentrated on a rotaryevaporator at up to 40° C. until the methanol was removed (2.75 h). Anaqueous solution of the product ˜1.5 L was obtained which had someprecipitate present (remaining trityl by-product). Additional water, 3L, was added to raise the overall volumes to approximately 6. Theaqueous solution was extracted with TBME (2×2.1 L, 2×3 vol) to removethe remaining trityl by-product. The pH of the aqueous solution wassubsequently adjusted from 1.13 to 9.89 with Ambersep 900 (OH form)resin (pre prepared) 650.2 g. After stirring for 40 minutes the pH wasunchanged. The slurry was filtered (Glass microfibre) and washed withwater (1.08 L, 1.5 vol). The resulting aqueous solution was washed withTBME twice and the pH adjusted with the pre-prepared Ambersep 900 resin.(˜0.8 wt) of resin was required to raise the pH from 1.36 to 10.47.After filtration the filter-cake was subsequently slurried in methanol(5 volumes) for 1 hour and the filtrates combined with the productfiltrate. Concentration of this water/methanol product solution followedby oven drying the resulting residue under high vacuum (for 72 hrs.)gave the crude product (299.6 g, 87.5%) as a yellow solid which could becrystallized as follows: crude 13 (1.0 wt) and methanol (4.5 vol) werestirred under nitrogen and the resulting suspension was heated to 60 to65° C. and then cooled to 50 to 55° C. and clarified through a glassmicrofiber filter followed by a line rinse of methanol (0.25 vol). Theclarified solution was cooled gradually to 20 to 25° C. over 1 to 1.5hour. Once the flask contents were within the temperature range andcrystallisation has initiated filtered ethanol (4.75 vol) was chargedover at least 45 minutes whilst maintaining the temperature at 20 to 25°C. The resulting slurry was cooled to 0 to 5° C. and then aged for atleast 15 hours at 0 to 5° C. to give pure 13 which was filtered as anoff-white to yellow solid (in a yield of 65 to 95% w/w.). ¹H-NMR (400MHz, DMSOd₆), δ 7.40 ppm, (d, J=7.3 Hz, 1H) CH cytosine, δ 7.20 ppm,(broad d, J=9.1 Hz, 2H) NH₂, δ5.74 ppm, (d, J=7.3 Hz, 1H) CH cytosine, δ5.30 ppm, broad s, 1H, CH, δ 5.15 ppm, (d, J=7.1 Hz, 1H) (OH), δ 5.00ppm, (d, J=6.1 Hz, 1H) (OH), δ 4.80 ppm, (q, J=5.3 Hz, 1H)(OH), δ 4.48ppm, (q, J=5.3 Hz, 1H) CH, δ 4.17 ppm, (dd, J=9.1 Hz, 3.8 Hz, 1H) CH, δ4.13 ppm, (dt, J=6.1 Hz, 5.8 Hz, 1H) CH, δ 3.91 ppm, (broad d, J=12.9Hz, 2.8 Hz, 1H) CH.

All documents (including patent applications, published patentapplications, and patents) cited herein or cited in any one of thepatent applications, published patent applications, and patentsincorporated by reference are hereby incorporated by reference in theirentirety and as if each had been individually incorporated.

The embodiments illustrated and discussed in this specification areintended only to teach those skilled in the art the best way known tothe inventors to make and use the invention. Nothing in thisspecification should be considered as limiting the scope of the presentinvention. All examples presented are representative and non-limiting.The above-described embodiments of the invention may be modified orvaried, without departing from the invention, as appreciated by thoseskilled in the art in light of the above teachings. It is, therefore, tobe understood that, within the scope of the claims and theirequivalents, the invention may be practiced otherwise than asspecifically described.

The invention claimed is:
 1. A process for preparingtert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(9) fromtert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(8), comprising: convertingtert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(8) to a boronic acid intermediate.
 2. The process of claim 1, furthercomprising: hydrolysing the boronic acid intermediate with silvertrifloromethane sulfonate to form a hydrolysate; and reacting thehydrolysate with1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) to formtert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(9).
 3. The process of claim 1, wherein the boronic acid intermediate isselected from a group consisting of[(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronicacid (9c-1) and[(3aR,6S,6aR)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy-tert-butyl-diphenyl-silane(9c-2).
 4. The process of claim 3, wherein the boronic acid intermediateis[(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronicacid (9c-1) and is formed by reacting thetert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(8) with trimethylborate.
 5. The process of claim 3, wherein the bonoricacid intermediate is[(3aR,6S,6aR)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy-tert-butyl-diphenyl-silane(9c-2) and is formed by reacting thetert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(8) with 4,4,5,5-tetramethyl-1,3,2 dioxaborolane.
 6. A process for thepreparation of4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one(13) comprising: convertingtert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(8) to a boronic acid intermediate; hydrolysing the boronic acidintermediate with silver trifloromethane sulfonate to form ahydrolysate; reacting the hydrolysate with1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) to formtert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(9); and isolating the4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one(13).
 7. The process of claim 6, wherein the boronic acid intermediateis[(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronicacid (9c-1).
 8. The process of claim 6, wherein the boronic acidintermediate is[(3aR,6S,6aR)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy-tert-butyl-diphenyl-silane(9c-2).
 9. The process of claim 6, further comprising: reacting thetert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(9) with tetra-n-butylammonium fluoride to form(3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(10).
 10. The process of claim 9, further comprising: reacting the(3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(10) with MsCl to form(3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (11).
 11. The process of claim 10, further comprising:reacting the(3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (11) with cytosine to form4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one(12).
 12. The process of claim 11, further comprising: reacting the4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one(12) with an acid to form 4-amino-1-((1 S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one(13).
 13. The process of claim 6, wherein the boronic acid intermediateis[(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronicacid (9c-1), further comprising: reacting the hydrolysate with1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) to formtert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(9); and reacting thetert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(9) with tetra-n-butylammonium fluoride to form(3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(10).
 14. The process of claim 13, further comprising: reacting the(3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(10) with MsCl to form(3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (11); reacting the(3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (11) with cytosine to form4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one(12); and reacting the4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one(12) with an acid to form 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one(13).
 15. The process of claim 6, wherein the boronic acid intermediateis[(3aR,6S,6aR)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy-tert-butyl-diphenyl-silane(9c-2), further comprising: reacting the hydrolysate with1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) to formtert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(9); and reacting thetert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane(9) with tetra-n-butylammonium fluoride to form(3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(10).
 16. The process of claim 15, further comprising: reacting the(3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(10) with MsCl to form(3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (11); reacting the(3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (11) with cytosine to form4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one(12); and reacting the4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one(12) with an acid to form4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one(13).
 17. A method of making4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one(13), comprising: reacting(3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (11) with cytosine to form4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one(12).
 18. The method of claim 17, further comprising: reacting (3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(10) with MsCl to form(3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (11).
 19. The method of claim 17, further comprising:reacting the4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one(12) with an acid to form4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one(13).
 20. The method of claim 17, further comprising: reacting(3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(10) with MsCl to form the(3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (11); and reacting the4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one(12) with an acid to form the 4-amino-1-((1 S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one(13).